Gallium (III) complexes, specifically tris (8-quinolinolato) gallium (III) (GaQ3) have demonstrated promise as antitumor agents for cancer treatment (see Jakupec, M. A. and Keppler, B. H., Current Topics in Medicinal Chemistry (2004) 4, 1575-1583; Bernstein, L. R., etallotherapeutic Drugs and Metal-Based Diagnostic Agents (2005) Chapter 14: 259-277; and Jakupec, M. A. and Keppler, B. A., Metal Ions in Biological Systems (2004) 425-448.) It is believed that the mechanism of action for these drugs is derived from induction of apoptosis. GaQ3 is a much stronger antitumor agent than simple gallium salts such as gallium nitrate (ca. 3× apoptosis induction). In the NCI 60 tumor panel cell line screen, GaQ3 exhibited a very different pattern of anti-tumor activity compared to gallium nitrate. GaQ3 is active against tumor cell lines resistant to gallium nitrate.
Gallium has been found to have benefits as an anti-inflammatory, for treatment of conditions related to calcium and bone metabolism and for tumor imaging as well as for cancer treatments.
In clinical trials with gallium nitrate, continuous infusion over 5-7 days was required to obtain optimal anti-tumor activity, indicating that a continuous systemic exposure to a certain level of gallium is necessary for efficacy (See Bernstein, 2005, supra). This mode of delivery is inconvenient and not practical. To solve this problem, a more convenient delivery method using oral dosing is proposed as the ideal route of administration to obtain the necessary continuous exposure. Additionally, continuous IV dosing is believed to be due to high serum levels of free gallium ion (the Ga3+ cation). This would be unavoidable with gallium salts such as gallium nitrate, but could be avoided with a complexed form of gallium such as GaQ3, provided it is stable in circulation in vivo.
A complexed form of gallium, such as GaQ3, is lipophilic and is more easily incorporated into tissues than gallium ion, improving bioavailability compared to simple gallium salts. Human serum binding studies show that GaQ3 binds very weakly to albumin, but strongly to transferrin (Tf), and is very stable at pH 7.4 in serum. (See Groessel, M. and Hartinger, C. G., Electrophoresis (2009) 30, 2720-2727 and Hummer, A. A. et al., J. Med. Chem. (2012) 55:5601-5613.)
Two properties of GaQ3 present challenging hurdles with respect to pharmaceutical development of an oral dosage form: very poor aqueous solubility, and lack of stability of the gallium complex in the acidic aqueous conditions in the stomach.
GaQ3 solubility in water is reported to be approximately 18-22 ppm. (See Timerbaev, A. R., Metallomics (2009) 1, 193-198.) Solubility is improved in isopropanol, acetone, DMSO and other nonaqueous solvents that are not practical for use in oral dosage forms.
The complexed structure of GaQ3 is disrupted completely at pH values below the pKa of 8-hydroxyquinoline (8-HQ; pKa=5.01). At this or lower pH values, the 8-HQ ligands are re-protonated, releasing the Ga3+ cation. This is undesirable because the benefits provided by the ligands (high lipophilicity, protein binding affinity and avoidance of free Ga3+ cation) are lost, thereby eliminating the advantegous GaQ3 structure required for successful oral delivery of gallium.
An oral GaQ3 clinical study was conducted in Europe with seven patients who were dosed with enteric coated tablets (See Hofheinz, R.-D., et al, Int. Journal of Clinical Pharmacology and Therapeutics (2005) 43:590-591 and Collery, P. et al, Metal Ions in Biology and Medicine (2006) 521-524.). In this study, the tablet core was a simple conventional formulation comprised of crystalline GaQ3 blended with cornstarch, lactose, polyvinylpyrollidone and magnesium stearate. The pressed tablet cores with dose strengths of 10 mg, 20 mg, and 30 mg were then pan-coated using a combination of Eudragit L and S polymers, plus acetone, isopropanol, triacetin and coloring agents for dosage strength differentiation. No attempt was made to reduce the particle size or crystalline nature of the GaQ3 beyond what was derived from the chemical synthesis of the compound (average particle size ca. 10 to 20 μm). While the results from this study indicated that the drug was well tolerated, confirmation of linear pharmacokinetics was not possible and an explicit dose recommendation for further study was not identified (See Timerbaev, 2009, supra). Although an attempt was made to inhibit the loss of the ligand structure using an enteric coating, it was postulated that a significant amount of the drug was not absorbed, thus dramatically limiting bioavailability.
The results from this first clinical evaluation of GaQ3 suggested that the low solubility of the crystalline compound possessing a particle size range normally considered adequate for a conventional formulation resulted in poor bioavailability and non-linear pharmacokinetics. The data indicated that although a portion of GaQ3 survived intact after transit through the stomach, the absorption observed was somewhat erratic through the intestine.
Thus, the challenge in the advancement of oral GaQ3 in clinical development is keeping the GaQ3 intact during transit through the stomach and releasing a more soluble form of GaQ3 within the intestinal tract where the compound is stable and can be absorbed intact.
This challenge is met by: 1) formation of a non-crystalline solid form of GaQ3 and 2) using an enteric coating on the final dosage form or subunits within the final form to prevent exposure to the destabilizing effects of gastric acid.